Obesity and Lipid Metabolism Disorders--Body Fat Loss
In humans, obesity can be defined as a body weight exceeding 20% of the desirable body weight for individuals of the same sex, height and frame (Salans, L. B., in Endocrinology & Metabolism, 2d Ed., McGraw-Hill, New York 1987, pp. 1203-1244; see also, R. H. Williams, Textbook of Endocrinology, 1974, pp. 904-916). In other animals (or also in humans) obesity can be determined by body weight patterns correlated with prolactin profiles given that members of a species that are young, lean, and "healthy" (i.e., free of any disorders, not just metabolic disorders) have daily plasma prolactin level profiles that follow a pattern characteristic of the species. This pattern is highly reproducible with a small standard deviation. Members of a species suffering from lipid and/or metabolism disorders, however, have aberrant prolactin profiles that depart from the normal (or healthy subjects') pattern by at least 1 SEM in at least two spaced apart time points or by at least 2 SEM (standard error of the mean) in at least one time point.
Obesity, or excess fat deposits, correlate with and may trigger the onset of various lipid and/or glucose metabolism disorders, e.g. hypertension, Type II diabetes, atherosclerosis, retinopathy etc.
Even in the absence of clinical obesity (according to the above definition) the reduction of body fat stores (notably visceral fat stores) in man, especially on a long-term or permanent basis would be of significant benefit, both cosmetically, physiologically and psychologically.
The reduction of body fat stores in domestic animals (as well as pets), especially on a long-term or permanent basis, would also obviously be of considerable economic benefit to man, particularly since farm animals supply a major portion of man's diet; and the animal fat may end up as de novo fat deposits in man.
Whereas controlled diet and exercise can produce modest results in the reduction of body fat deposits, prior to the cumulative work of the present inventors (including the prior co-pending patent applications and issued U.S. patents referred to below), no truly effective or practical treatment had been found for controlling obesity or other lipid metabolism disorders.
Hyperlipoproteinemia is a condition in which the concentration of one or more of cholesterol- or triglyceride-carrying lipoproteins (such as chylomicrons, very low density lipoproteins ("VLDL"), and low-density lipoproteins ("LDL") in plasma exceeds a normal limit. This upper limit is generally defined as the ninety-fifth percentile of a random population. Elevated levels of these substances have also been positively correlated with atherosclerosis and the often resulting cardiac infarction, or "heart attack", which accounts for approximately half of all deaths in the United States. Strong clinical evidence has been presented which correlates a reduction in plasma lipoprotein concentration with a reduced risk of atherosclerosis (Noma, A., et al., Atherosclerosis 49:1, 1983; Illingworth, D. and Conner, W., in Endocrinology & Metabolism, McGraw-Hill, New York 1987). Thus, a significant amount of research has been devoted to finding treatment methods which reduce levels of plasma cholesterol and triglycerides. High LDL and/or VLDL accompanied by high triglyceride levels in the blood constitute most important risk factors for atherosclerosis. Reduction of one or both of lipoproteins and triglycerides in the blood would reduce the risk of atherosclerosis and cardiac arrest, or retard their development.
Another subset of the plasma lipoproteins found in vertebrates are high density lipoproteins, HDL ("HDL"). HDL serve to remove free cholesterol from the plasma. A high HDL concentration, as a percentage of total plasma cholesterol, has been associated with a reduced risk of atherosclerosis and heart disease. Thus, HDL are known in the lay press as "good" cholesterol. Therefore, therapeutic strategies involve attempts both to reduce plasma LDL and VLDL content (that is, reduce total plasma cholesterol), and to increase the HDL fraction of total plasma cholesterol. Several lines of research indicate that simply increasing HDL is of benefit even in the absence of LDL or VLDL reduction: Bell, G. P. et al., Atherosclerosis 36:47-54, 1980; Fears, R., Biochem. Pharmacol. 33:219-228, 1984; Thompson, G., Br. Heart J. 51:585-588, 1989; Blackburn, H. N.E.J.M. 309:426-428, 1983.
Current therapies for hyperlipoproteinemias include a low fat diet and elimination of aggravating factors such as sedentary lifestyle. If the hyperlipoproteinemia is secondary (i.e., incident to e.g., a deficiency of lipoprotein lipase or LDL receptor, various endocrine pathologies, alcoholism, renal disorders, or hepatic disorders) then control of the underlying disease is also central to treatment. Hyperlipoproteinemias are also treated with drugs, which usually alter the levels of particular components of the total plasma cholesterol, as well as reduce the total plasma lipid component. Among the most recently introduced drugs to treat hyperlipoproteinemia is lovastatin (MEVACOR.RTM.) which selectively inhibits an enzyme involved in cholesterol production, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. This drug specifically reduces total cholesterol and can cause a modest (5-10%) increase in HDL concentrations. However, benefits from these therapies vary from subject to subject.
Moreover, use of the HMG-CoA enzyme inhibitor is sometimes accompanied by side effects such as liver toxicity, renal myoglobinuria, renal shutdown, and lenticular opacity. The risk of such side effects necessitates close monitoring of the patients (e.g., liver function is tested monthly).
Another drug prescribed against hyperlipoproteinemia is clofibrate. The effectiveness of clofibrate also varies from subject to subject and its use is often accompanied by such side effects as nephrotic syndromes, myalgia, nausea, and abdominal pain.